Pediatric Pneumonia Podcast

The History, Challenges, and Future Development of Pediatric Pneumococcal Conjugate Vaccines

Todd A. Florin, MD, MSCE; Richard Malley, MD


June 07, 2023

This transcript has been edited for clarity. For more episodes, download the Medscape app or subscribe to the podcast on Apple Podcasts, Spotify, or your preferred podcast provider.

Todd A. Florin, MD, MSCE: Hello. I'm Dr Todd Florin, an associate professor at Northwestern University's Feinberg School of Medicine and director of research for the Division of Emergency Medicine at the Ann and Robert H. Lurie Children's Hospital of Chicago. Welcome to the Medscape InDiscussion podcast series on pediatric pneumonia. Today we'll discuss updates on vaccines in pediatric pneumococcal disease.

As this audience well knows, there have been virtually no advances in medicine, with the exception of clean water supply, that have had as dramatic an impact on the health of children as vaccines. The advent of pediatric pneumococcal conjugated vaccines (PCVs) in 2000 is yet another example. With PCVs, the landscape of pneumococcal disease in children and in adults has been dramatically modified, with a plummeting in the number of cases caused by serotypes included in the vaccine. At the same time, despite these remarkable achievements, there remain gaps in our ability to protect children against pneumococcal infections. We will address this in our segment today with our guest, Dr Rick Malley.

Dr Malley is the Kenneth McIntosh Chair in Pediatric Infectious Diseases at Boston Children's Hospital and professor of Pediatrics at Harvard Medical School. Dr Malley regularly attends on the Pediatric Infectious Diseases service at Boston Children's Hospital, providing consultation on inpatients. Welcome to InDiscussion, Rick. How are you doing today?

Richard Malley, MD: I'm fine, Todd. Nice to see you.

Florin: Great to see you. What do you think are some of the most exciting changes in healthcare in your field that you've seen aside from vaccine development, which we'll talk about later today?

Malley: I think one of the greatest advances is the use of technology in medicine in all of its forms. We rotate with residents, fellows, and junior attendings, and they all have so much information about unusual cases, case reports, and studies that are literally at their fingertips or at the touch of their phones. I really think that has transformed the way we practice medicine today, because the availability of information, data, and commentary is really something that did not exist when I was in training many years ago.

Florin: Yes, I totally agree and feel that sentiment as well. The speed at which information is coming out is just remarkable. I think it contrasts with some of the discussion that we're going to have today, which is the much longer journey toward the development of vaccines over time. I think back to the history of pneumonia, and we can go back to the early 1900s when William Osler called pneumonia the "Captain of the Men of Death," taking over for consumption. Pneumonia was a major cause of mortality until the advent of antibiotics for pneumococcus in the early 20th century. Over time, that led to the development of vaccines and vaccine technology, which was really a game changer in public health. I'd like to start with a discussion of why we think vaccines work, particularly against bacteria like pneumococcus. Can you talk about how these vaccines work against these pathogens?

Malley: Sure. In a very simplistic way, it's helpful to think of pneumococcus as an M&M. You have M&M's of various colors, and all of these colors represent different sugar coatings on the surface of the bacterium. What was initially recognized was that immunity to one of those sugars — having antibodies that are directed against a particular color of that M&M — was protective against that serotype, that capsid, or a strain of pneumococcus but not so much against others. In fact, in most cases, there was no protection at all. This basically meant that very early on, people acknowledged that to produce a vaccine against this organism, you had to target the sugar coating. You may have to use many of them because a lot of these different sugar coats exist.

Florin: I really like that analogy, and I think it speaks to the importance of these polysaccharides as the virulence factors for the bacteria. There are differences in the way that adults and children will respond. Can you talk more about these differences between adult and pediatric responses and what technology has been used specifically in pediatric vaccines?

Malley: One of the things that is so remarkable about children is that, by and large, they remain healthy despite the fact that they have not seen a lot of these pathogens before, unlike adults. So children are pretty good resisters against infection. One of the things that children just don't do very well, particularly for the kids under age 2, is make antibodies to boring structures like sugars. Polysaccharides are just repeating units of sugars, and those are very blurring immunologically. They do not elicit any type of reaction. There are no bells and whistles that you see in an individual who is exposed, say, to a protein. The children really don't respond very well to polysaccharides as opposed to adults. Even adults don't respond that well to pure sugars — they need help. The help that is remarkably used in vaccines is to trick the immune system into responding to the sugar in many ways, as if it were a protein. The trick was developed many years ago by conjugating polysaccharides to proteins. One of the people who developed this was my mentor, Porter Anderson Jr. You trick the baby into responding to the sugar as if it were a protein, which makes the baby much more responsive to the vaccination. It generates immunity that is long lasting, and it generates the all-important memory response that will protect that child even months after the primary series has been accomplished.

Florin: Fascinating. I think it's great that we have talked about the fundamentals of how these vaccines work. The impact of these vaccines is what I'd like to talk about next. When I was in training, we already had many of these vaccines in circulation. PCV7 and the Haemophilus influenzae type b (Hib) vaccine (H. flu) were in use. Can you talk about the impact that these vaccines have had on the health outcomes and disease prevalence in children for these really deadly diseases?

Malley: I was an intern at Boston Children's Hospital in 1990. In the first year, I became very accustomed to being called down to the emergency room to take care of children who were struggling with a very aggressive infection, invasive Hib. Hib would cause meningitis, periorbital cellulitis, and septicemia. It was a very dangerous organism, and one in 200 children under age 2 would suffer from some form of invasive disease due to this organism. I became very good at taking care of those kids, particularly those with meningitis, where the care was complicated. A year later, essentially 1 year after the H. flu conjugated vaccine that was developed by individuals at the NIH and at Boston Children's Hospital that then moved to Rochester, this vaccine eliminated Hib disease from every single country that implemented universal vaccination in children. From one year to the next, this disease that I had become relatively comfortable taking care of had essentially disappeared from our emergency rooms. To be honest and slightly personal, it was that realization that made me decide to focus my career and my research efforts on vaccine development, because I had never seen anything quite as dramatic as the impact of one intervention on eliminating suffering and death in children.

Florin: Wow. That perspective is so important to remember and for us in the newer generation to actually hear about. We are not seeing this level of disease that you saw. To bring it back to pneumococcus, I think back to the beginning of my training. In the pre-vaccine era, any time a clinician saw a child come in with a fever for more than a few days greater than 39 °C and with a white count greater than 20 and below 20,000, we would get blood cultures and treat with ceftriaxone prophylactically because of the risk of occult bacteremia. That had virtually disappeared with the advent and progression of the pneumococcal vaccine. Can you talk about how the pneumococcal vaccine came about, including the initial studies of PCV7 and the history of the subsequent versions of the pneumococcal vaccine that had been developed?

Malley: The PCV7 story is a fascinating one because it was a study that could only have been accomplished in the US exactly for the reason you mentioned, which is that in the United States, we had a very concerted effort to treat every case we could identify of occult pneumococcal bacteremia. That basically meant that every child who presented with a temperature over 39 °C and had a high white count would get a blood culture and ceftriaxone. But it meant that investigators would then have a very large pool with pneumococcal bacteremia. Even if the patients weren't critically ill or very sick, they were febrile with bacteria floating around in their blood, which is not a good thing. Most of those kids would generally recover very uneventfully. This enabled investigators to enroll about 37,000 kids in the northern California region and study PCV7, which was a conjugated vaccine that included the seven most common serotypes, the sugars that were prevalent in Northern California. This was a phenomenal achievement where you could basically show efficacy of a vaccine against a disease that we all took care of but in any other country would have been impossible because the process of culturing every child with a fever of 39 °C was mostly an American thing. It was not done in other countries where they waited for more signs of illness and criticality. This was a dramatic achievement and resulted in the licensure of the first PCV.

Florin: When that vaccine was licensed and widely disseminated, what was the overall impact? Clearly there was an impact on individuals who were vaccinated. We've heard a lot in the media over the last 3 years about herd immunity and what that means. Can you talk about the impact of this vaccination on the individual and on broader society?

Malley: This vaccine had a dramatic impact on protecting the child against the seven serotypes that were included in the initial vaccine. It also protected the adult population, particularly the older adult population, in some countries more than others, and we don't totally understand why. Very soon after the licensure of PCV7, the Centers for Disease Control and Prevention (CDC) reported that for every case of pneumococcal disease that we were preventing in a child who was being vaccinated with this vaccine, we were also preventing two cases of invasive pneumococcal disease in older adults, even though they were not being vaccinated with the PCV. This is a case where for every child you protect, you also protect two older adults who could suffer terrible consequences from pneumococcal disease, and you were doing it at no cost to the older adult. They did not need to be vaccinated. They did not need to see their doctor. They did not need to remember to get the vaccine. They were getting protected by the indirect effects of this vaccine. That was a tremendous accomplishment of this conjugated vaccine.

Florin: Absolutely. After PCV7 came out, there have been subsequent vaccines, including PCV10 and PCV13. Can you talk about the rationale for why these additional serotypes were added to the PCV, and where we are now and where we might need to go in the near future?

Malley: One of the problems with the M&M analogy is that there are a hundred different colors of pneumococcus that can circulate. Many of them don't often cause disease in humans. On the other hand, there are several that can. When you knock down the seven most prevalent types, we noticed that not only did they no longer cause invasive disease, but we also couldn't even find those seven serotypes when we swabbed the nose of children 2 to 3 years after the advent of PCV in 2000. They were replaced by other colors, other polysaccharides. One of them in particular, 19A, emerged around that time. It was multi-drug resistant, highly lethal, and very dangerous. That prompted vaccine manufacturers to recognize that they needed to make a larger valency vaccine, which led to Prevnar 13 in the US. There was also Synflorix, which was a 10-valent vaccine that was developed mostly in Europe. Other companies then started getting into this effort. We now have a PCV15 vaccine that was recently approved in adults and in children. It covers the same 13 serotypes as Prevnar 13, but they've added two additional important serotypes. The same company that made PCV13 has now an approved vaccine in adults that contains 20 serotypes, and they are also applying for approval in children. There is this race, if you will, to try to see how many we can cover and how many we need to cover to avoid the serotype replacement problem, which at some point could have limited the impact of pneumococcal vaccine.

Florin: Do you think there's ever a possibility for a pan-pneumococcal vaccine, a vaccine that would cover all of the approximately 100 serotypes?

Malley: It's music to my ears, but it's somewhat painful because it's been going on in my career for a very long time. The idea is that if you get rid of the strategy of just targeting every sugar that you can think of and focus instead on some common proteins that pneumococcus cannot cause disease without, you might be able to create a pan-pneumococcal vaccine. This is a very arduous, difficult task. Many people have worked on this. I have spent a large part of my career on this as well. So far, there has not been a success out of these efforts. That doesn't mean that a very bright young physician or scientist couldn't come up with a strategy that will work, but that is ultimately one way to really control this disease. One example that your audience will know is the meningococcal B vaccine, which is based on proteins and whose effects go beyond meningococcal B, because the other serogroups of meningococcus also contain those proteins and have been shown to be affected by the meningococcal B vaccine strategy. There is hope, I believe, that somebody will be able to develop this. I'm just not sure it will be me.

Florin: Can you expand on what the technical and physical challenges are to targeting those proteins for a pan-pneumococcal vaccine? What are some of the biggest challenges that you face as a scientist developing this vaccine against these potential targets?

Malley: One of them is a very simple and at the same time difficult one, which is that even though we all recognize that pneumococcal disease is still an important problem because of the serotype replacement issue, it is now a relatively rare disease, fortunately. In many cases, it's a disease that's hard to diagnose. In many cases of pneumonia in children, we don't really know the cause of the pneumonia. We just assume it could be pneumococcal or with some other bacterium. That leads to a difficulty in designing a clinical trial to truly assess whether your pan-pneumococcal vaccine will work because you need a certain number of cases that you can diagnose categorically to conduct a clinical trial. In a way, we are somewhat victims of our own success. There's less pneumococcal disease in the US, so it makes it very difficult to study a pan-pneumococcal vaccine, even though the disease is still a problem. That is one issue. The other issue, which is scientific, is you have to find the right antigen. To follow up on the M&M analogy, there are components of the chocolate of the M&M that are probably very protective. Many people, including my lab, have been trying to figure out which components would be most protective against pneumococcal infection. That's an area of intense study still today.

Florin: Yes, I appreciate the clinical trial challenges that vaccine scientists face for that pan-pneumococcal vaccine. I think that those same challenges exist for those of us looking to optimize antimicrobial therapy for kids in terms of trying to figure out which subset of this large sample of children with pneumonia require antibiotics and which do not. It gets to this fundamental issue that we simply do not have the diagnostic tests available, and the prevalence has gotten so low that you can't actually know which kids have pneumococcus vs those who do not. It's a fundamental challenge in the work that all of us as pneumonia scientists face on a regular basis. I would like to talk about this idea of serotype replacement. Why does it happen, and what are the most concerning serotypes at the moment that we need to worry about in children?

Malley: The reason that happens, I think, is just a Darwinian struggle. There are different pneumococcal types with different capsular types. When you knock down some, it opens up an ecological niche for the others to grow in. Plus, they're very well adapted — maybe even better now that the other ones are gone. In this process, serotype 3 has eluded us, even though it's included in the current conjugate vaccine that we use in the US, and the impact on a population level has been close to zero. In fact, the CDC assigned an efficacy of the type 3 component of the vaccine as zero, which is a big problem. It's a huge problem in older adults. It is still a significant issue in pediatric populations. I think a very important target for any future development of a pneumococcal vaccine is to improve our coverage of that serotype. We don't know exactly how to do it. It might mean you need to generate more antibody to the capsule than the current vaccine does. The other idea that many people have is perhaps this is an ideal case scenario to study a combination of capsular antibodies and antibodies to proteins, or the chocolate component of type 3 to try to target it in two separate ways.

Florin: I'd like to end by bringing this back to something you had mentioned: Finding pneumococcus in the nose of children and which serotypes we're finding. It's well established that depending on which study you look at, anywhere from 30% to 50% of young children are colonized with pneumococcus. It becomes very difficult to distinguish which of those kids with colonization are going to go on to develop pneumococcal disease vs which kids will eventually continue to go through life without developing pneumococcal disease despite having pneumococcus in their noses at a young age. Can you talk about this relationship between pneumococcal colonization and the development of invasive pneumococcal disease and how vaccines have affected that relationship between colonization and infection?

Malley: We often say that it's impossible to get pneumococcal infection without prior colonization. That's generally assumed to be the case. For example, I think we've all envisioned that if an accident took place where there was a breach in the central nervous system (CNS), the organism could come straight from the outside world into the brain. Fortunately, those cases are quite rare. Even in cases of cerebrospinal fluid (CSF) leaks, it's generally colonization of the nose that bypasses the bloodstream and goes straight into the brain. I think colonization is a sine qua non for subsequent infection. Studies that are relatively old now suggested that it was in the first few weeks after acquisition of a new strain that a child's risk of developing disease, such as otitis media, was at its peak. We believe the same is probably true for other bacteria like meningococcus, where it's in the early stages when the host has not yet figured out how to control that organism. For this reason, many people have argued that perhaps the best way to develop a pan-pneumococcal vaccine would be to figure out a way to limit colonization — or reduce or abrogate colonization as much as possible. Many people have looked at nasal vaccines and other strategies than antibodies to try to reduce it. I think that could, in theory, be a very effective strategy. Your audience knows that people are evaluating this. In COVID, for example, vaccines administered through the nasal mucosa might generate local immunity that would prevent COVID from even causing asymptomatic infection. That could be the same thing for pneumococcus if we could figure out the right vaccine and the right route of administration.

Florin: Rick, we've spent this time together talking a lot about some of the technical aspects of vaccination and the enormous benefits. Fortunately in the United States, pneumonia is not a major cause of mortality. Pneumonia has a high prevalence. It can cause morbidity in some, but mortality due to pneumonia in previously healthy kids in the United States is very low. However, we know that is not the case globally. Pneumonia remains a leading killer of children, particularly children younger than 5 years of age in low-to-middle income countries. It seems that vaccination could be a major strategy to reduce that mortality in these areas of the world. Can you talk about getting vaccines into arms of kids in lower-to-middle income countries? What are some of the challenges? Where are we at, and what's the future hold for this critically important population?

Malley: Unfortunately, Todd, we've experienced this very recently with the COVID vaccines as well, where the developed world had vaccines against COVID in record time. I think people like me who've worked on vaccines for almost 30 years never imagined that we would have a vaccine that was so effective in a short 11 months after the virus was first identified and sequenced. The developing world is still in a situation where these vaccines have not been made widely available. The same has been true historically with the H. flu conjugate vaccine. It took a long time — over 10 years — for the vaccines to reach certain countries in the developing world. The same is true with pneumococcus, although there is a very strong movement from the Bill & Melinda Gates Foundation and governments to broaden access to these lifesaving vaccines to the developing world. Some of the issues with access relate to how the vaccine is made. This is a very expensive vaccine. You must have extraordinary talent and very sophisticated strategies to make these vaccines. One example is the PCV7 vaccine has over 500 quality control tests that have to be all validated before you could get your vaccine licensed. When we are talking about 13- or 20-valent vaccines, those numbers will just multiply. Another issue is that these vaccines are administered by injection, and almost half the cost of a vaccine comes from the needle and the syringe that is required to inject this lifesaving substance into a child. These are expensive vaccines, difficult to make, and the developing world is not in the process of making them right now. For all these reasons, alternative strategies should be sought at the same time as we try to increase the accessibility and availability of these vaccines in the developing world. That's a very important effort. We always understood, and COVID made it even clearer, that if we don't take care of people everywhere, we end up with problems locally. We should really care and try to save as many lives as possible everywhere.

Florin: I think that's a great way to wrap up our conversation. Today we've talked with Dr Rick Malley about pneumococcal vaccination, its history, its challenges, and some of its future directions. I think we can all agree that the development of vaccines has enormous impact, and it's really one of the greatest public health accomplishments in history. However, despite all the progress that has been made, there are still some really important issues to work through, including expanding serotype coverage of the pneumococcal vaccine and thinking about ways that we can get this technology to the people who most need it in the developing world. The future is bright and exciting, and that's largely due to the efforts of scientists and vaccinologists like yourself, Rick. I'm excited about what is to come in the near future in this field to help save lives through the prevention of these invasive bacteria through vaccination. Thank you all for tuning in. Please take a moment to download the Medscape app to listen and subscribe to this podcast series on pediatric pneumonia. This is Dr Todd Florin for Medscape InDiscussion.


Pediatric Pneumonia

Masking the Pathogen: Evolutionary Strategies of Fungi and Their Bacterial Counterparts

Priming and Induction of Haemophilus Influenzae Type B Capsular Antibodies in Early Infancy by Dpo20, an Oligosaccharide-protein Conjugate Vaccine

About Pneumococcal Vaccines

Haemophilus Influenzae Type B Vaccine (Rx)

Haemophilus Influenzae

Efficacy, Safety and Immunogenicity of Heptavalent Pneumococcal Conjugate Vaccine in Children. Northern California Kaiser Permanente Vaccine Study Center Group

Streptococcus Pneumoniae Serotype 19A: Worldwide Epidemiology

Pneumococcal Vaccine 13-valent (Rx)

Pneumococcal Polysaccharide Protein D-conjugate Vaccine (Synflorix; PHiD-CV)

Pneumococcal Vaccine 15-valent (Rx)

Development of Next Generation Streptococcus pneumoniae Vaccines Conferring Broad Protection

Meningococcal Group B Vaccine (Rx)

Serotype Replacement After Introduction of 10-valent and 13-valent Pneumococcal Conjugate Vaccines in 10 Countries, Europe

Sugar-coated Killer: Serotype 3 Pneumococcal Disease

Prevalence of Nasopharyngeal Pneumococcal Colonization in Children and Antimicrobial Susceptibility Profiles of Carriage Isolates

Community-acquired Pneumonia

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